KR20140075711A - Sulfonic Acid Salts of Heterocyclylamide-Substituted Imidazoles - Google Patents

Abstract

The invention relates to sulfonic acid salts of heterocyclylamide-substituted imidazoles, to solvates and hydrates thereof, to their use for the treatment and / or prevention of diseases, to treat diseases and / To their use for the preparation of medicaments for the prevention, in particular for their use as antiviral agents, in particular against cytomegalovirus.

Description

Sulfonic Acid Salts of Heterocyclylamide-Substituted Imidazoles < RTI ID = 0.0 >

The present invention relates to salts of the compounds of formula (I)

In this formula,

R ¹ is methyl, ethyl, butyl, or cyclopropylmethyl,

R ² is phenyl, said phenyl is phenyl substituted with a substituent selected from the group consisting of trifluoromethoxy and difluoromethoxy,

R ³ is hydrogen, methyl, chlorine, methoxy, or trifluoromethyl.

The present invention relates to a process for their preparation, to their use for the treatment and / or prophylaxis of diseases, to their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment of cytomegaloviruses , As anti-viral agents.

The compounds of formula (I) are known, for example, from WO 2006/089664 and have been developed by the applicant as potential candidates for antiviral efficacy agents, particularly for combating human cytomegalovirus (HCMV) infection. During development, this material showed an inadequate solubility in aqueous solvents as well as in strong polar solvents. The problem with solubility was further highlighted in that the compound also showed inadequate solubility under conditions in which the compound was present in the stomach (about 0.1 M HCl, pH ~ 1), wherein the process was carried out in- situ formation.

Accordingly, the object of the invention is to describe a salt which shows a considerably improved solubility relative to the free base of the compound of formula (I). Furthermore, these salts should also be stable for long periods of time under common storage conditions. In particular, the compound should not show any increased moisture absorption. In addition, in the presence of a dilute HCl solution, the salt should be converted only slowly to the HCl salt to ensure as fast and uniform release as possible, even under the conditions present on the human.

Surprisingly, it has been found that the organic sulfonic acid salts of the compounds of formula (I) show good solubilities in addition to the free bases, as compared to other salts of the broad spectrum of compounds of formula (I). Moreover, these salts have also demonstrated the long-term stability required for medical applications. In addition, salts according to the invention have also been shown to exhibit high and uniform solubility under conditions comparable to those on humans.

The subject of the invention is a salt of a compound of formula (I) with an organic sulfonic acid, or a solvate or hydrate thereof.

Within the scope of the invention, the salt of the organic sulfonic acid is an adduct of the reaction of the compound of formula (I) with the organic sulfonic acid. In this connection, the compound of formula (I) and the organic sulfonic acid may be present in any ratio. In this case, the ratio is preferably an integer (for example, 1: 1, 1: 2, 1: 3, 3: 1, 2: 1). In this case, these salts can be prepared by direct reaction of the compound of formula (I) with the organic sulfonic acid or by the exchange of the counterion after preparation of the other acid salt of the compound of formula (I).

Within the scope of the invention, the form of the compound according to the invention for forming a complex by coordination with a solvent molecule is referred to as "solvate ". Hydrates are a special form of solvate in which coordination with water is carried out.

Within the scope of the invention, the salt is preferably the organic sulfonic acid is methanesulfonic acid.

Within the scope of the invention, the dimesylate salt is particularly preferred.

Within the scope of the invention, salts of the following formula are preferred:

Within the scope of the invention, in particular, powder-XRD diffraction shows the crystalline N- (1-methyl (2-methyl) pyrrolidone), which shows characteristic peaks at about 6.37, 11.77, 12.56, 17.17, 18.81, 20.34, 21.47, 23.04, 35.46 degrees 2 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1 H-imidazol-4-yl) -N '- [4-trifluoromethoxy Phenyl] urea dimesylate is preferred.

Within the scope of the invention, crystalline N- (1-methyl-2 - {[4- (5-methylpyridin- 2- yl) piperazin- 1 -yl] -carbonyl} -1 H-imidazol -4-) -N '- [4- trifluoromethoxyphenyl] are preferable to the urea di-mesylate was added.

Salts according to the invention are generally prepared by the reaction of a compound of formula (I) with an organic sulfonic acid in a solvent.

The salts according to the invention can additionally be prepared by the reaction of the acid salt of the compound of formula (I) with a source of the sulfonate anion of the organic sulfonic acid, which is not a salt of the organic sulfonic acid in the solvent.

In the latter case, the source of the sulfonate anion may be a salt of an organic sulfonic acid or an organic sulfonic acid.

The subject matter of the invention is thus furthermore a process for the preparation of an organic sulfonic acid salt of a compound of formula (I), which comprises reacting a salt of a compound of formula (I), which is not a compound of formula (I) or an organic sulfonic acid, Lt; / RTI > with an organic sulfonate anion source.

The solvent is preferably selected from those methods which provide a good balance between the solubility of the organic sulfonic acid or sulfonate anion source and the salt of the compound of formula (I) that is not a salt of a compound of formula (I) or of an organic sulfonic acid . Preferably, in the solvent used, the salt according to the invention should be practically insoluble as possible. Optionally, the salt according to the invention may, however, also be precipitated by the addition of an anti-solvent.

Examples of the solvent used in the preparation of the salt according to the invention include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; Ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-diethoxyethane, dioxane or tetrahydrofuran; Hydrocarbons such as benzene or toluene; Or other solvents such as acetone, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, heptane, dimethyl sulfoxide or dimethylformamide.

Optionally, an anti-solvent is added to precipitate the salt according to the invention. Examples of counter-solvents include so-called water and alcohols such as methanol, ethanol, or propanol.

The salts obtainable according to the invention can additionally be further processed, for example, recrystallized or micronized, in order to further adapt their physical properties to the application field.

The heterocycylamide-substituted imidazoles used for the preparation of the salts according to the invention are known and can be prepared, for example, according to the method described in WO 2006/089664.

In particular, the preparation of the heterocyclylamide-substituted imidazoles used can be carried out by reacting a compound of the formula (II)

(III) with a compound of formula (III) in the presence of a dehydrating agent by reaction of the first step with a base of the formula (III) wherein R ¹ and R ² are as defined above and R ⁴ is methyl or ethyl Is performed by

(Wherein R < ³ > is as defined above).

The reaction of the first step is usually carried out in an inert solvent, preferably within a temperature range of 0 < 0 > C until refluxing of the solvent occurs under normal pressure.

The base is, for example, an alkali hydroxide such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, or an alkali carbonate such as cesium carbonate, sodium carbonate or potassium carbonate. In this case, sodium hydroxide is preferable.

Inert solvents include, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene; Ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude fractions; Or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, or a mixture of water and solvents. As a solvent, a mixture of ethanol and water is preferred.

The second stage reaction is usually carried out in an inert solvent, optionally in the presence of a base, preferably under normal pressure, at a temperature ranging from -70 ° C to 40 ° C.

As the dehydrating agent, in this connection, for example, N, N'-diethyl-, N, N'-dipropyl-, N, N'- diisopropyl-, N, N'-dicyclohexylcarbodiimide Such as N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) Carbodiimide; Or a carbonyl compound such as carbonyldiimidazole; Or a 1,2-oxazolium compound such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl- Ethoxy carbonyl-1,2-dihydroquinoline, or an acylamino compound such as propanephosphonic acid anhydride or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) N, N, N ', N'-tetramethyluronium hexafluorophosphate (N, N'-tetramethyluronium hexafluorophosphate) (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazole (HATU), or 1-hydroxybenzotriazole (HOBt) or benzotriazol-1-yloxytris (Dimethylamino) phosphonium hexa By Luo phosphate (BOP) or a mixture of the latter (with base) it is suitable.

The base may be, for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate or potassium bicarbonate; Or organic bases such as trialkylamines such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine or DBU, DBN or pyridine, N-methylmorpholine is preferred.

Condensation with propanephosphonic acid anhydride (T3P) is preferably carried out in the presence of N-methylmorpholine (NMM).

Inert solvents include, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene; Ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude fractions; Or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, in the case of a solvent which can be mixed with water, .

Compounds of formula (II) are known and, in a first step, compounds of formula (IV) below are reacted with a reducing agent,

(As described herein, R ¹ and R ⁴ are as defined above), a compound of formula H ₂ NR ² (V) under acid derivative present in the second step (in which R ² is the same as defined above) and reacting, or the second phase Can be prepared by reacting a compound of formula OCN-R < ² > (VI) wherein R < ² > is as defined above.

In this case, the reaction is usually carried out in an inert solvent in the first step and preferably in a temperature range of 0 ° C until reflux of the solvent occurs under normal pressure up to 3 bar.

Reductants include, for example, palladium on activated carbon and hydrogen, formic acid / triethylamine / palladium on activated carbon, zinc, zinc / hydrochloric acid, iron, iron / hydrochloric acid, ferric sulfate / hydrochloric acid, sodium sulfide, sodium disulfide, Ammonium hydrogen polysulfide, sodium boron hydride, sodium borate / nickel chloride, tin dichloride, titanium trichloride, or Raney nickel and aqueous hydrazine solutions, the Raney nickel and aqueous hydrazine solutions, palladium on activated carbon and hydrogen, Formic acid on carbon / triethylamine / palladium is preferred.

Inert solvents include, for example, ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude fractions; Or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, in the case of water-miscible solvents, a mixture of the compound and water. As the solvent, methanol, ethanol and isopropanol are preferable, and in the case of Raney nickel and aqueous hydrazine solution, tetrahydrofuran is preferable.

The reaction in the second step according to the first variant is usually carried out under normal pressure in an inert solvent, preferably at temperatures ranging from room temperature to 40 < 0 > C.

The carbonic acid derivative is, for example, N, N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl chloroformate, or chloroformic acid-4-nitrophenyl ester, Imidazole is preferred.

Inert solvents include, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene; Ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude fractions; Or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, in the case of a solvent which can be mixed with water, Is preferable.

The reaction in the second step according to the second variant is usually carried out under normal pressure in an inert solvent, optionally in the presence of a base, preferably at room temperature, until refluxing of the solvent takes place.

Inert solvents include, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene; Ethers such as diethyl ether, methyl-tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude fractions; Or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine. Tetrahydrofuran or methylene chloride is preferred.

The base can be an alkali metal carbonate such as, for example, cesium carbonate, sodium carbonate or potassium carbonate, or potassium-tert-butanolate or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, Ethylamine is preferred.

The chemistry of formula (IV) is known, and compounds of formula (VII) are prepared by reacting fumaric nitric acid, concentrated nitric acid, acetic anhydride, Nitric acid, or other mixed ratios of sulfuric acid and nitric acid

(VII)

(VII)

(Wherein R ¹ and R ⁴ are as defined above).

The compounds of formulas (III), (IV), (V) and (VII) are known and can be synthesized from the corresponding extracts according to known methods.

The preparation of the heterocyclylamide-substituted imidazoles used for the preparation of the salts according to the invention is explained in more detail by the exemplary method of the synthesis diagram below. In this regard, the synthesis diagram below is purely illustrative and does not limit the method.

Composite Figure:

Salts according to the invention exhibit antiviral efficacy primarily against cytomegalovirus (CMV), particularly human cytomegalovirus (HCMV), while representing the herpes virus group (Herpesviridae). They are therefore suitable for the treatment and / or prophylaxis of diseases, primarily viral infections, in particular the viral infections mentioned herein and the infectious diseases thereof. Herein, a viral infection is defined as both an infection by a virus as well as a disease caused by a viral infection.

Salts according to the invention can be used based on their special properties for the preparation of medicaments suitable for the prevention and / or treatment of diseases, in particular viral infections.

The following may be mentioned as the categories to be noted:

1) Treatment and prevention of HCMV infection in AIDS patients (retinitis, pneumonia, gastrointestinal tract infection).

2) Treatment and prevention of cytomegalovirus infections in bone marrow and organ transplant patients (these often result in life-threatening levels of HCMV pneumonia, HCMV encephalitis as well as gastrointestinal and systemic HCMV infection).

3) Treatment and prevention of HCMV infection in newborns and infants.

4) Treatment of acute HCMV infection in pregnant women.

5) Treatment of HCMV infection in patients immunosuppressed with cancer and cancer treatment.

HCMV-mediated tumors (J. Cinatl, et al., FEMS Microbiology Reviews 2004 , 28, 59-77) for the treatment of patients with HCMV-positive cancer.

Salts according to the invention for the manufacture of medicaments are preferably used so as to be suitable for the prevention and / or treatment of typical herpes viruses, particularly cytomegalovirus, especially human cytomegalovirus infection.

Based on their pharmacological properties, it is also possible, if necessary, to use other active ingredients, in particular valacanclovir, ganciclovir, valacyclovir, acyclovir, together with antiviral active ingredients such as foscarnet, cidofovir and related derivatives, the salts according to the invention can be used for the treatment and / or prophylaxis of viral infections, in particular HCMV infections.

Another subject of the invention is the use of the salts according to the invention in a method for the treatment and / or prevention of diseases, preferably viral infections, in particular infections of the human cytomegalovirus (HCMV) or other representative herpes virus group.

Another subject of the invention is the use of the salts according to the invention for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

Another subject of the invention is the use of the salts according to the invention for the preparation of medicaments for the treatment and / or prevention of diseases, in particular the diseases mentioned above.

Another subject of the invention is a method for the treatment and / or prevention of a disease, in particular of the above-mentioned diseases, using a salt according to the invention as an antiviral effective amount.

Salts according to the invention may have systemic and / or topical efficacy. For this purpose they can be administered by any suitable route such as oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, transdermal, conjunctival, efferent, or by means of implants or stents.

In these methods of administration, the salts according to the invention may be administered in any suitable dosage form.

In the case of oral administration, the salts according to the invention are delivered in a fast and / or modified manner and the forms of administration in which the compounds according to the invention are contained in crystalline and / or amorphized and / For example, tablets (coated tablets or uncoated tablets having a gastric-resistant or slowly-dissolving or non-soluble coating to control the release of the compounds according to the invention), rapidly dissolving tablets or films / wafers in the mouth, Coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols, or solutions are suitable in the art.

The parenteral administration may be carried out either by bypassing the absorption phase (e.g., by intravenous, intraarterial, intracardiac, intraspinal, or lumbar means), or by including an absorption step (e.g. intramuscular, subcutaneous, Lt; / RTI > by intraperitoneal means). For parenteral administration, injection and infusion formulations, for example in the form of solutions, suspensions, emulsions, lyophilized or sterile powders, are suitable as dosage forms.

In other modes of administration, for example, the mode of inhalation of the drug (e.g., powder inhaler, atomizer), dots, nasal drops, nasal sprays; Tablets administered in the tongue, sublingual, or buccal; Suitable are films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milks, pastes, foams, sprays, implants or stents Do.

Salts according to the invention can be converted into the recited dosage form. This can be done by mixing with inert, non-toxic and pharmaceutically compatible auxiliary agents known in the art. Such adjuvants include, for example, excipients such as excipients such as microcrystalline cellulose, lactose, mannitol, solvents such as liquid polyethylene glycols, emulsifiers, and dispersing or wetting agents such as sodium dodecyl sulfate, polyoxy sorbitan oleate, , Antioxidants (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxide), and flavorings and / or fodders (e.g., polyvinylpyrrolidone), synthetic and natural polymers .

Within the scope of the invention, a salt according to the invention of from 5 to 12.5 mg / ml, 50 to 150 mg / ml of hydroxypropyl-beta-cyclodextrin, 0.5 to 2.0 mg / ml of sodium acetate, Agents consisting of pharmaceutically innocuous adjuvants are preferred.

Another subject of the invention is a medicament containing one or more salts according to the invention together with one or more inert, non-toxic and pharmaceutically compatible auxiliary agents, as well as their use for the purposes mentioned above.

In general, for intravenous administration, it is advantageous to administer in an amount of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg (based on body weight) Proved. For oral administration, the metering is usually about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg, on a weight basis.

Nevertheless, it may be necessary, optionally, to deviate from the doses mentioned above, in particular based on body weight, the method of administration, the individual behavior for the active ingredient, the type of preparation and the time or interval at which administration is carried out. Thus, in some cases, it may be less than the above-mentioned minimum dose, in other cases it may be exceeded to the maximum dosage. If large doses are administered, it may be desirable to have several separate doses throughout the day.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be described in more detail with reference to embodiments and necessary drawings.

1 shows the powder-XRD diffractogram of Example 1. Fig.

Percentages in the following experiments and examples are percent by weight and parts by weight unless otherwise specified. The solvent ratio, dilution ratio, and concentration information of the liquid / liquid solution are each related to the volume.

< Examples >

Abbreviations Used:

Ex. Example

TLC thin-layer chromatography

DMF N, N -dimethylformamide

DMSO dimethylsulfoxide

d. Th. Theoretical

EI electron impact ionization (in MS)

ESI Electrospray ionization (in MS)

h Time

HPLC High Pressure, High Performance Liquid Chromatography

LC-MS liquid chromatography-bond mass spectrometry

MS mass spectrometry

NMR nuclear magnetic resonance

RP-HPLC reverse phase HPLC

RT room temperature

R _t retention time (in HPLC)

TBTU O- (benzotriazol-1-yl) -N, N, N ' , N' Tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

HPLC - and LC - MS  Way:

Method 1 ( LC - MS ):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100;

Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;

Eluent A: water 1 L + 0.5% formic acid 50%

Eluent B: acetonitrile 1 L + 0.5% formic acid 50%;

Gradient: 0.0 min 90% A 2.5 min 30% A 3.0 min 5% A 4.5 min 5% A;

Flow rate: 0.0 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min;

Oven: 50 캜;

UV detection: 208-400 nm.

Method 2 ( LC - MS ):

Instrument: Micromass Quartz LCZ with HPLC Agilent Series 1100;

Column: Pinomenex Synergy 2 [mu] Hydro-RP Mercury 20 mm x 4 mm;

Eluent A: water 1 L + 0.5% formic acid 50%

Eluent B: acetonitrile 1 L + 0.5% formic acid 50%;

Gradient: 0.0 min 90% A 2.5 min 30% A 3.0 min 5% A 4.5 min 5% A;

Flow rate: 0.0 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min;

Oven: 50 캜;

UV detection: 210 nm.

Method 3 ( LC - MS ):

MS device type: Micromass ZQ;

HPLC instrument type: Waters Alliance 2795;

Column: Pinomenex Synergy 2 [mu] Hydro-RP Mercury 20 mm x 4 mm;

Eluent A: water 1 L + 0.5% formic acid 50%

Eluent B: acetonitrile 1 L + 0.5% formic acid 50%;

Gradient: 0.0 min 90% A 2.5 min 30% A 3.0 min 5% A 4.5 min 5% A;

Flow rate: 0.0 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min;

Oven: 50 캜;

UV detection: 210 nm.

Method 4 ( LC - MS ):

MS device type: Micromass ZQ;

HPLC instrument type: HP 1100 series;

UV DAD;

Column: Pinomenex Synergy 2μ Hydro-RP Mercury 20 mm x 4 mm;

Eluent A: water 1 L + 0.5% formic acid 50%

Eluent B: 1 L of acetonitrile + 0.5 ml of 50% formic acid

Gradient: 0.0 min 90% A 2.5 min 30% A 3.0 min 5% A 4.5 min 5% A;

Flow rate: 0.0 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min;

Oven: 50 캜;

UV detection: 210 nm.

Method 5 (Analytical HPLC ):

Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 mu m;

Eluent A: water + 0.5% perchloric acid (70%),

Eluent B: acetonitrile;

Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B, 9.2 min 2% B,

Flow rate: 0.75 ml / min;

Column temperature: 30 占 폚;

Detection: UV 210 nm.

Starting compound

Example  1A

(Cyclopropylmethyl) -4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-imidazole-

Step 1

1- (Cyclopropylmethyl) -4-nitro-1H-imidazole-2-carboxylic acid ethyl ester

15 g (81 mmol) of 4-nitro-lH-imidazole-2-carboxylic acid ethyl ester are dissolved in 165 ml of DMF under argon with 13.13 g (97.2 mmol) cyclopropylmethyl bromide and 22.4 g (162 mmol) Potassium was stirred at 80 &lt; 0 &gt; C for 1 hour. After cooling, the reaction mixture was diluted with water and extracted four times with ethyl acetate. The combined organic phases were washed once with water, three times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo by evaporation. The crystalline residue was immediately reused for the next reaction.

Yield: 17.59 g (70% of theory)

LC-MS (method 1): R _t = 2.02 min.

MS (ESI < ⁺ >): m / z = 240 [M + H] < ⁺

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 8.2 (s, 1H), 4.4 (q, 2H), 4.3 (d, 2H), 1.4 (m, 4H), 0.55 (q, 2H) , 0.45 (q, 2H) ppm.

Step 2

4-Amino-1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester

 3.89 g (16.26 mmol) of 1- (cyclopropylmethyl) -4-nitro-1H-imidazole-2-carboxylic acid ethyl ester were dissolved in 50 ml of THF and mixed with a spatula tip filled with Raney nickel. The reaction mixture was hydrogenated with hydrogen at ambient temperature using a hydrogenation apparatus. The catalyst was filtered off and the filtrate was concentrated by evaporation in vacuo. The evaporation residue was immediately reused for the next reaction.

Yield: 3.46 g (100% of theory)

LC-MS (method 2): R _t = 1.21 min.

MS (ESI ⁺ ): m / z = 210 [M + H] &lt; ^{+ &}

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 6.55 (s, 1H), 4.55 (s, 2H), 4.2 (q, 2H), 4.1 (d, 2H), 1.25 (tr, 3H) , 1.2 (m, 1H), 0.5 (q, 2H), 0.3 (q, 2H) ppm.

Step 3

Amino] -1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester

 7.49 g (35.8 mmol) of 4-amino-1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester was dissolved in 18 ml of THF under argon with 6 g (35.8 mmol) Phenylisocyanate, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated by evaporation in vacuo, in which case the crystallized product was stirred up with 40 ml of ethyl acetate and then sucked up.

Yield: 11.1 g (82% of theory)

LC-MS (method 1): R _t = 2.66 min.

^{MS (ESI +): m /} z = 376 [M + H] +

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 9.45 (s, 1H), 8.0 (d, 1H), 7.35 (s, 1H), 7.3 (d, 1H), 7.2 (dd, 1H) 2H), 4.25 (s, 3H), 1.3 (tr, 3H), 1.25 (m, .

Step 4

Carbonyl) amino] -1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid

 Amino] -1- (cyclopropylmethyl) -lH-imidazole-2-carboxylic acid ethyl ester was reacted with 10.6 g (28.1 mmol) of 4 - [({[4- (trifluoromethoxy) phenyl] Suspended in 158 ml of ethanol. While cooling with ice, 16.4 ml of water and 6 ml (112 mmol) of a 50% aqueous sodium hydroxide solution were added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo by evaporation. The residue was collected in 100 ml of isopropanol and mixed with 100 ml of 1N hydrochloric acid while cooling with ice. The crystals were sucked up and vacuum dried at 40 &lt; 0 &gt; C.

Yield: 9.85 g (100% of theory)

LC-MS (method 3): R _t = 1.74 min.

MS (ESI ⁺ ): m / z = 349 [M + H] &lt; ^{+ &}

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 9.4 (s, 1H), 8.0 (d, 1H), 7.3 (s, 1H), 7.25 (d, 1H), 7.2 (dd, 1H) , 4.25 (d, 2H), 2.25 (s, 3H), 1.25 (m, 1H), 0.55 (q, 2H), 0.35 (q, 2H) ppm.

Example  2A

Amino] carbonyl) amino] -1H-imidazole-2-carboxylic acid ethyl ester

Is prepared in the same manner as in Example 1A.

Yield: 2.05 g (96% of theory)

LC-MS (method 3): R _t = 1.96 min.

MS (ESI < ⁺ >): m / z = 387 [M + H] < ⁺

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 9.0 (s, 1H), 8.9 (s, 1H), 7.55 (d, 2H), 7.3 (s, 1H), 7.25 (d, 1H) , 4.35 (tr, 2H), 1.7 (hexane, 2H), 1.25 (heavy line, 2H), 0.9 (tr, 3H) ppm.

Example  3A

Methyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-imidazole-

Amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (synthesized in the same manner as in Example 1A, step 3 or described in Tetrahedron Lett. 2003, 44, 1607 ] And synthesized according to the literature cited therein) was mixed with 1.46 g (7.21 mmol) of 4- (trifluoromethoxy) phenylisocyanate in 50 ml of THF under argon and then stirred overnight at room temperature. The reaction mixture was filtered, the filtrate was concentrated in vacuo via evaporation and chromatographed.

Yield: 860 mg (62% of theory)

LC-MS (method 4): R _t = 2.41 min.

MS (ESI ⁺ ): m / z = 373 [M + H] &lt; ^{+ &}

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 8.98 (bs, 2H), 7.55 (m, 2H), 7.36 (s, 1H), 7.29 (m, 2H), 4.28 (q, 2H) , 3.91 (s, 3H), 1.30 (t, 3H).

Example  4A

Methyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-imidazole-

Amino] -1H-imidazole-2-carboxylic acid ethyl ester (Example 3A) in the presence of 835 mg (2.13 mmol) Was suspended in 5 ml of ethanol and 12 ml of tetrahydrofuran. While cooling with ice, 2 ml (25 mmol) of a 50% aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature overnight, then acidified with 1N hydrochloric acid while cooling with ice. This solution was extracted with dichloromethane. The organic phase was concentrated via evaporation in vacuo. The residue was purified by preparative HPLC.

Yield: 346 mg (44% of theory)

LC-MS (method 3): R _t = 1.62 min.

MS (ESI ⁺ ): m / z = 345 [M + H] &lt; ^{+ &}

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 9.33 (bs, 1H), 8.98 (bs, 1H), 7.55 (m, 2H), 7.30 (s, 1H), 7.28 (m, 2H) , &Lt; / RTI &gt; 3.90 (s, 3H).

Example  5A

1-ethyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-imidazole-

Prepared in the same manner as in Example 4A.

Yield: 425 mg (91% of theory)

LC-MS (method 4): R _t = 1.94 min.

^{MS (ESI +): m /} z = 359 [M + H] +

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 10.3 (bs, 1H), 7.67 (m, 2H), 7.24 (s, 1H), 7.20 (m, 2H), 4.45 (q, 2H) , &Lt; / RTI &gt; 1.33 (t, 3H).

Example  6A

4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1-methyl-1H-imidazole-

Prepared in the same manner as in Example 4A.

Yield: 964 mg (81% of theory)

HPLC (method 5): R _t = 3.57 min.

MS (ESI ⁺ ): m / z = 327 [M + H] &lt; ^{+ &}

^{1 H-NMR (400 MHz,} CDCl 3): δ = 8.9 (s, 1H), 8.8 (s, 1H), 7.5 (d, 2H), 7.3 (s, 2H), 7.1 (t, 1H), 7.09 (d, 2 H), 3.9 (s, 3 H).

Example  7A

1- (5-methylpyridin-2-yl) piperazine

Step 1

1- (tert-Butyloxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine

Under an argon atmosphere, 2.50 g (19.6 mmol) of 2-methyl-5-chloropyridine and 4.38 g (23.5 mmol) of N- (tert-butyloxycarbonyl) -piperazine were dissolved in 50 ml of anhydrous toluene. Thereafter, 2.26 g (23.5 mmol) of sodium-tert-butylate, 0.37 g (0.59 mmol) of BINAP and 0.36 g (0.39 mmol) of tris (dibenzylideneacetone) Lt; / RTI &gt; for 12 hours. After cooling, the reaction mixture was mixed with diethyl ether, washed three times with saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography (cyclohexane / ethyl acetate 9: 1).

Alternatively, the coupling reaction can also be carried out using palladium- (II) -acetate as a catalyst.

Yield: 5.27 g (97% of theory)

LC-MS (method 3): R _t = 1.26 min.

MS (ESI ⁺ ): m / z = 278 [M + H] &lt; ^{+ &}

^{1 H-NMR (300 MHz,} CDCl 3): δ = 8.02 (d, 1H), 7.34 (dd, 1H), 6.59 (d, 1H), 3.55 (m, 4H), 3.45 (m, 4H), 2.21 (s, 3H), 1.49 (s, 9H).

Step 2

1- (5-methylpyridin-2-yl) piperazine

After dissolving 3.47 g (12.5 mmol) of 1- (tert-butyloxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine in 10 ml of dioxane, Was mixed with 31 ml (125 mmol) of hydrogen chloride. The mixture was stirred at room temperature for 2 hours. It was then concentrated by evaporation, the residue was alkalized with 1 M sodium hydroxide solution and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated by evaporation and dried under vacuum.

Alternatively, the compound of formula 7A in practice can be isolated in the form of the hydrochloride salt.

Feeding: 2.18 g (98% of theory)

LC-MS (method 4): R _t = 0.38 min.

MS (ESI ⁺ ): m / z = 177 [M + H] &lt; ^{+ &}

^{1 H-NMR (300 MHz,} CDCl 3): δ = 8.02 (d, 1H), 7.32 (dd, 1H), 6.59 (d, 1H), 3.45 (m, 4H), 3.00 (m, 4H), 2.20 (s, 3 H).

Example  8A

Yl} -N ' - [4- (trifluoromethyl) piperazine-1-yl] Methoxy) phenyl] urea

After 1.50 g (4.36 mmol) of the compound of Example 4A was dissolved in 30 ml of DMF, 1.82 g (5.66 mmol) of O- (benzotriazol-1 -yl) -N, N, N ' Tetramethyluronium tetrafluoroborate (TBTU) and 266 mg (2.18 mmol) of 4-dimethylaminopyridine. 925 mg (5.66 mmol) of 1- (pyridin-2-yl) -piperazine was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by RP-HPLC.

Yield: 1.79 g (83% of theory)

LC-MS (method 1): R _t = 1.83 min.

MS (ESI ⁺ ): m / z = 490 [M + H] &lt; ^{+ &}

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 8.89 (bs, 2H), 8.12 (d, 1H), 7.55 (m, 3H), 7.29 (m, 2H), 7.20 (s, 1H) , 6.88 (d, IH), 6.68 (dd, IH), 4.02 (bs, 2H), 3.77 (s, 3H), 3.71 (bs, 2H), 3.58 (bs, 4H).

Example  9A

Yl) -N ' - [4- (5-methylpyridin-2-yl) piperazin- 1 -yl] (Trifluoromethoxy) phenyl] urea

5.6 g (26.14 mmol) of the compound of Example 7A and 13.22 g (130.7 mmol) of N-methylmorpholine were added to a solution of 9.0 g (26.14 mmol) of the compound of Example 4A in 110 ml of ethyl acetate, The reaction mixture was cooled to 0 &lt; 0 &gt; C. 16.63 g (52.26 mmol) of propanephosphonic anhydride (T3P) was added to the reaction solution over 90 minutes and the resulting suspension was stirred at the same temperature for an additional 10 minutes. The reaction mixture was then heated at 20 &lt; 0 &gt; C for 60 min and then stirred overnight at the same temperature. Unreacted T3P was quenched by the addition of 45 ml of water and the reaction mixture was stirred for an additional 10 minutes. The phases were then separated and the organic phase was washed several times with water (3 x 45 ml) and adjusted to pH 5. The combined aqueous phases were washed once more with ethyl acetate and then washed twice with 45 ml of aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated by evaporation. The crude product thus obtained was recrystallized from ethanol to give the final product as a pale yellow solid.

Yield: 8.42 g (64% of theory)

LC-MS (method 4): R _t = 2.01 min.

MS (ESI ⁺ ): m / z = 504 [M + H] &lt; ^{+ &}

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 8.92 (bs, 2H), 7.99 (d, 1H), 7.54 (m, 2H), 7.42 (dd, 1H), 7.28 (m, 2H) , 7.20 (s, IH), 6.80 (d, IH), 4.00 (bs, 2H), 3.77 (s, 3H), 3.72 (bs, 2H), 3.51 (bs, 4H), 2.16

Example  10A

Yl] -N ' - [4- (5-chloropyridin-2-yl) piperazin- 1 -yl] carbonyl} (Trifluoromethoxy) phenyl] urea

Prepared in the same manner as in Example 5A from Example 9A.

Yield: 55 mg (68% of theory)

LC-MS (method 4): R _t = 2.76 min.

^{MS (ESI +): m /} z = 538 [M + H] +

^{1 H-NMR (300 MHz,} DMSO-d 6): δ = 8.97 (bs, 1H), 8.92 (bs, 1H), 8.14 (d, 1H), 7.65 (dd, 1H), 7.54 (m, 2H) , 7.28 (s, IH), 6.92 (d, IH), 4.16 (q, 2H), 3.97 (bs, 2H), 3.72 1.32 (t, 3 H).

Example  11A

- [4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -1-methyl-1H-imidazol- Methoxy) phenyl] urea

Are prepared in the same manner as in Example 4A to Example 9A.

Yield: 35 mg (58% of theory)

LC-MS (method 3): R _t = 2.24 min.

MS (ESI ⁺ ): m / z = 519 [M + H] &lt; ^{+ &}

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 8.89 (bs, 2H), 7.53 (m, 2H), 7.28 (m, 2H), 7.19 (s, 1H), 6.92 (m, 2H) , 6.84 (m, 2H), 4.05 (bs, 2H), 3.75 (m, 5H), 3.69 (s, 3H), 3.08 (bs, 4H).

Example  12A

2-yl) piperazin-1-yl] -carbonyl} - (2-methyl- Imidazol-4-yl) urea

Prepared in the same manner as in Example 6A from Example 9A.

Yield: 17 mg (29% of theory)

LC-MS (method 4): R _t = 1.70 min.

^{MS (ESI +): m /} z = 486 [M + H] +

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 8.84 (bs, 1H), 8.77 (bs, 1H), 7.98 (d, 1H), 7.47 (m, 2H), 7.42 (dd, 1H) , 7.18 (s, 1H), 7.11 (t, 1H), 7.10 (m, 2H), 6.80 (d, 3.50 (bs, 4H), 2.16 (s, 3H).

The example compounds of Table 1 are prepared in the same manner as in Example 8A.

Table 1

Embodiment

Example  One

N- (1- methyl-2 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1 H-imidazol-4-yl) -N '- [ 4-trifluoromethoxyphenyl] urea dimesylate

All manipulations were performed under a nitrogen-cover gas atmosphere. In the reaction vessel, 3,202 g of the compound of Example 9A (6.36 mol, 1 eq.) Were mixed with a mixture consisting of 15 L of THF and 1 L of water. The resulting suspension was slowly heated to &lt; RTI ID = 0.0 &gt; 60 C &lt; / RTI &gt; and stirred at the same temperature for 30 minutes. After adding 1,252 g of methanesulfonic acid (13.03 mol, 2.05 eq.) To the resulting yellowish solution, a solution of N- (l-methyl-2 - {[4- (5-methyl-pyridin- - yl] were inoculated into [4-trifluoromethoxyphenyl] urea di-mesylate-carbonyl} -1 H-imidazol-4-yl) -N '. Crystalline N- (1- methyl-2 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1 H-imidazol -4-) -N ' - [4- &lt; / RTI &gt; trifluoromethoxyphenyl] urea dimesylate was added over another 2 hours 30 L of THF. The suspension was slowly cooled to 20 &lt; 0 &gt; C and stirred at the same temperature for an additional 12 hours. The crystals formed were collected by vacuum filtration and the reactor was washed with THF followed by n-heptane, which was then used to wash the crystals. Finally, the crystals were dried with a filter under vacuum and a nitrogen stream.

4,262 g (yield: 96.4%, purity > 99%) of the desired dimesylate salt.

^{1 H-NMR (400 MHz,} DMSO-d 6): δ = 9.07 (s, 1H), 8.98 (s, 1H), 7.99 (s, 1H), 7.92 (d, 1H), 7.56 (d, 2H) (S, 3H), 7.41 (d, 1H), 7.33-7.24 (m, 3H), 4.18 (s, br., 2H), 3.92-3.69 (m, 9H), 2.43-2.39 ).

The X-ray diffraction diagram shown in Fig. 1 was recorded using a Rigaku MiniFlex powder-XRD spectrometer.

The compounds of Example 8A as well as the compounds of Examples 10A to 15A can be converted to the dimesylate salt in the same manner.

Solubility experiment

20 mg of the compound of Example 1, as well as the citrate, maleate, sulfate and tartrate of the compound of Example 9A for comparison of the compound; Chloride salt of Example 9A prepared with 1, 2, and 4 equivalents of hydrochloric acid; And the free base was weighed in an HPLC glass equipped with a magnetic stirrer. 1 ml of H ₂ O was added, and the HPLC glass was sealed. The resulting suspension was stirred at 25 &lt; 0 &gt; C overnight. To determine the amount of dissolved material, the suspension was filtered through a pipette fine filter, and the resulting filtrate was diluted 1: 4 and analyzed by HPLC. HPLC analysis was performed using an isocratic mixture of acetonitrile and H ₂ O + 0.1% TFA (3: 7 ratio) in a Dionex Luna RP18 (100A) -column with dimensions 5 μm 50 x 4.6 mm .

As a result of the measurement of the solubility, the values shown in Table 2 below were determined.

Table 2

These values clearly show that the salt of Example 1 also shows improved solubility in aqueous media compared to other salts of the compound of Example 9A.

Solubility under humane conditions

In order to determine the solubility under simulated conditions on human stomach, the citrate, tartrate and corresponding free base of Example 9A, as well as the salt of Example 1, in an aqueous sodium chloride solution (0.2 wt%) set to pH 1.2 with hydrochloric acid Was stirred for 5 hours. This sample was processed as described above and the amount of free base in solution was determined by HPLC. Values corresponding to solubility under simulated human conditions are shown in Table 3 below.

Table 3

This table clearly shows that the salts according to the invention show improved solubility under conditions simulating human stomach. In this regard, it should be noted that even after the solution has been left for a long time, a freshly-shaped suspension is observed. The latter can be expected to result from the formation of a nearly insoluble chloride salt of Example 9A. The formation of this observed insoluble chloride salt is not believed to be serious, but the latter (mainly when used according to Example 1) is delayed in initiation, initially present as a metastable supersaturated solution. This is noted as an additional advantage that can be achieved with the use of the salts according to the invention in the manufacture of medicaments.

Moisture absorption

The salt of Example 1 was stored at about 46% relative humidity in the atmosphere and in a purified form at 24 캜 to measure the moisture absorption of the salt according to the invention. In this case, after a storage period of about 2 days, the salt of Example 1 exhibited a weight gain of less than 0.11%, indicating a moisture absorption suitable for drug use.

B. Evaluation of physiological efficacy

The in vitro action of the compounds according to the invention for the replication of HCMV (human cytomegalovirus) can be seen in the antiviral assay below:

HCMV  Fluorescence reduction test

The test compound was used as a solution in 50 mM concentration (mM) in dimethylsulfoxide (DMSO). For reference compounds, for example, Ganciclovir, Foscarnet, Cidofovir, or other compounds of Example 9A may be used. On the day before the start of the test, 1.5 x 10 ⁴ human phallic fibroblasts (NHDF cells / well) were seeded in 200 μl cell culture in 96-well plates (black of translucent bottom) in the B2-G11 wells. In the wells at the edge positions of each 96-well plate, only 200 μl of culture medium was filled in order to avoid the edge effect. On the day of the test run, the cell culture was aspirated in B2-G11 wells of each 96-well plate and replaced with 100 μl of virus suspension (MOI: 0.1-0.2). The virus used was a recombinant HCMV containing the expression cassette of green fluorescent protein (GFP) in the viral genome (HCMV AD 169 RV-HG, EM Borst, K. Wagner, A. Binz, B. Sodeik, and M. Messerle, 2008, J. Virol , 82 : 2065-2078). After an incubation period of 2 hours at 37 ° C and 5% CO ₂ , the virus inoculum was aspirated and all wells except column 3 wells were filled with 200 μl of cell culture. Column 2 was provided for virus control without further treatment. The wells in column 3 were filled into each well for duplicate measurements with 300 [mu] l of test material (diluted in cell culture medium). The concentration of the corresponding anti-viral material in column 3 is the expected EC ₅₀ The value was ~ 27x concentration. The test material of column 3 was transferred to each right column of the column with 100 [mu] l of each column, mixed with 200 [mu] l of cell culture already existing, and diluted 1: 3 8 times over a 96-well plate. In this way, three antiviral agents were tested in duplicate. The plate was at 37 ℃ / 5% CO ₂ and incubated for 7 days. Next, all wells of the plate were washed three times with PBS (phosphate buffered saline) and then filled with 50 占 퐇 of PBS. The GFP intensity of each well of the 96-well plate was then determined using a fluorescence recognition instrument (FluoBox; Bayer Technology Services GmbH; filter setting: GFP, Ex 480 nm, Em 520 nm) Respectively. The EC ₅₀ of the anti-HCMV material can be determined from the measurements thus obtained.

EC ₅₀ (GFP-RA) = concentration of substance (μM) that reduces GFP fluorescence by 50% compared to untreated virus control in infected cells.

Representative in vitro activity data for compounds according to the invention are presented in Table 4:

Table 4

Embodiments of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

refine:

Furtherance:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidine (PVP 25) (BASF Company, Ludwigshaffen (Ludwigshafen, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Produce:

A mixture of the active ingredient, lactose and starch was granulated with a 5% solution of PVP in water (m / m).

After drying, the granules were mixed with magnesium stearate for 5 minutes. This mixture was pressed with a conventional tablet press (see above for tablet formulation). A compression force of 15 kN was used as a guide value for compression.

Suspensions that can be administered orally:

Furtherance:

1,000 mg of the compound of Example 1, 1,000 mg of ethanol (96%), 400 mg of Rhodigel (FMC Corp., xanthan gum of Pennsylvania, USA), and 99 g of water.

10 ml oral suspension corresponding to a separate dose of 100 mg of the compound according to the invention.

Produce:

After the Lodigel was suspended in ethanol, the active ingredient was added to the suspension. Addition of water during stirring was carried out. The mixture was stirred for about 6 hours until the swelling of the Lodigel was completed.

Solutions which can be administered intravenously:

Furtherance:

1000 g of water for injection containing 5.53 g of the compound of Example 1, 10% (w / v) hydroxypropyl-beta-cyclodextrin (Aldrich), and 985 mg of sodium acetate.

Produce:

The compound according to the invention was dissolved in water with stirring and the pH of the solution was set to a pH of about 3.94 with sodium acetate. The solution was sterilized by filtration (pore diameter 0.22 mu m) and transferred to a heat-sterilized fusion flask in sterile condition. The latter was sealed with an infusion plug and the rim was closed.

Claims (14)

A salt of a compound of the formula (I) with an organic sulfonic acid or a solvate or hydrate thereof.

In this formula,
R ¹ is methyl, ethyl, butyl, or cyclopropylmethyl,
R ² is phenyl substituted with a substituent selected from the group consisting of trifluoromethoxy and difluoromethoxy,
R ³ is hydrogen, methyl, chlorine, methoxy, or trifluoromethyl. The salt of claim 1, wherein the organic sulfonic acid is methanesulfonic acid. 3. The salt of claim 2 wherein said salt is a dimesylate salt. A salt according to claim 3 having the formula:

The crystalline-N- (1-methyl-2 - {[4- (4-fluorophenyl) (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1 H-imidazol-4-yl) -N '- [4- trifluoromethoxy-phenyl] urea di-mesylate. (1-methyl-2 - {[4- (5-methylpyridin-2-yl) piperazin- 1 -yl] -carbonyl } -1 H - imidazol-4-yl) -N '- [4- trifluoromethoxy-phenyl] urea di-mesylate. A process for the preparation of a compound of formula (I), which comprises reacting an acid salt of the compound of formula (I) with an organic sulfonic acid or an organic sulfonic acid salt ion source in a solvent, Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; 7. A salt according to any one of claims 1 to 6 for use in a method for the treatment and / or prophylaxis of diseases, particularly viral infections, preferably infections of other representatives of the HCMV or herpes virus group. A medicament containing a salt according to any one of claims 1 to 6 together with one or more inert, non-toxic pharmaceutically acceptable auxiliary. The pharmaceutical composition according to claim 9, which comprises 5 to 12.5 mg / ml of a salt according to any one of claims 1 to 6, 50 to 150 mg / ml of hydroxypropyl-beta-cyclodextrin, 0.5 to 2.0 mg / ml Of sodium acetate, as well as water, and optionally other pharmaceutically harmful adjuvants. Use of a salt according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of a viral infection, preferably HCMV, or another representative of the group of herpes viruses. Use of a salt according to any one of claims 1 to 6 in a method for the treatment and / or prevention of a disease, particularly a viral infection, preferably an infection by HCMV or other representatives of the herpes virus group. 11. A medicament according to claim 9 or 10 for use in a method for the treatment and / or prevention of a viral infection, preferably an infection by HCMV or other representatives of the herpes virus group. An antiviral effective amount of at least one salt according to any one of claims 1 to 6, a medicament according to claim 9 or 10, or a medicament obtained according to claim 11 or 12, A method of combating infection by human and animal viral infections, preferably HCMV or other representatives of the herpes virus family, comprising administering to the animal.

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